Project Summary/Abstract Research has shown that immune function is associated with depression, although the reasons for this link are unclear. One important step is to investigate neural processes, given that there is research implicating abnormal neural function in depression, and associations between inflammation, brain activity, and depressed mood. However, this has not yet been explored in adolescents, even though early adolescence is a sensitive developmental period of brain growth and organization. Immune dysfunction may have a strong effect on brain function during this time, which in turn, may increase risk for elevated depressed mood; however, the temporal direction of these associations remains unclear. In addition, pubertal development has also shown to be associated with both brain development and the onset of mental health symptoms, and to moderate the association between immune function and depressive symptoms. Puberty may be especially salient for girls, as rates of depression increase to twice that of boys starting at puberty, and female sex hormones are associated with a stronger immune response. My pilot data shows that earlier developing girls have a negative correlation between inflammation and brain activity in the insula, striatum and anterior cingulate cortex during emotional face processing, which in turn is negatively associated with depressive symptoms. However, longitudinal research in this area is lacking, making it difficult to determine if immune function and changes in brain function precede changes in mood and the emergence of clinical depression during adolescence, and how pubertal timing and tempo may affect these associations. Development of brain connectivity has also not been explored. My training goals for the proposed K01 are to train in fMRI and resting-state connectivity analysis, and to understand longitudinal developmental neuroscience models relevant to psychoneuroimmunology, which will establish me as an independent investigator. These goals will be met by having support from an established and experienced mentoring and advisor team, and through the research aims of this study, which are to prospectively examine immunology, brain function and connectivity, and depression in girls in early adolescence, and to determine the effect that puberty has on these associations. Specifically, the study will collect data from an established longitudinal cohort of N=170 adolescent girls, at 11, 12.5, and 14 years old, which does not yet have any specific research questions regarding immune functioning. First, at each time point, I will assess cross-sectional associations between inflammation, brain activity and connectivity, and depressive symptoms, and the moderating effect of pubertal timing. Second, I will investigate longitudinal developmental patterns, such as changes in brain activity and connectivity as a mediator of the association between immune function and depression, or prediction of trajectories of these variables. Third, I will conduct a sub-study of 64 girls to examine inflammatory responses to and brain activity during an fMRI social-evaluative stressor. Overall, this study will identify mental health outcomes of inflammation from a developmental and neurobiological perspective, and will establish me as an independent research scientist in this area.